Dementias tend to be characterized by cognitive disorders and often by depression. A particularly devastating dementia is Alzheimer's disease (AD). AD affects more than 30% of humans over 80 years of age, and as such, represents one of the most important health problems in developed countries (Evans et al., J.A.M.A. 262: 2551-2556 (1989); Katzman and Saitoh, FASEB J. 280: 278-286 (1991)). This neurodegenerative disorder of unknown etiology is clinically characterized by gradual impairment of cognitive function. The large buildup of intracytoplasmic neurofibrillary tangles and neurite plaques observed histopathologically in AD plausibly leads to degeneration of affected nerve cells. At least one study showed decreases in histamine and histidine levels in frontal, temporal and occipital cortices and in the caudate nucleus of brains from AD patients examined post mortem (Mazurkiewics and Wsonwah, Can. J. Physiol. Pharmacol., 67:75-78 (1989)).
Histamine is a chemical messenger involved in various complex biological actions. It is widely distributed in the plant and animal kingdoms. In mammals, including man, it occurs mainly in an inactive bound form in most body tissues. When released, histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Histamine (4(2-aminoethyl) imidazole) is a base. Its chemical structure is: ##STR1##
Histamine receptor pharmacology has revealed three subtypes of receptors which mediate (or are associated with) the activity of histamine. These receptors are most commonly referred to as H.sub.1, H.sub.2, and H.sub.3. The most recently discovered of these receptors is the H.sub.3 histamine receptor. Early studies suggested the presence of another histamine receptor when it was demonstrated that histamine inhibits its own synthesis and release in brain slices by a negative feedback process operating at the level of histaminergic nerve-endings (see, for example, Arrang, J.M. et al. Nature 302:832-837 (1983)). More recently, the H.sub.3 receptor has been shown to function as a pre-synaptic autoreceptor inhibiting histamine synthesis and histamine release from neurons, especially in the central nervous system (Arrang, et al. Nature 327:117-123 (1987)). The presence of H.sub.3 receptors in peripheral tissues has also been reported and here too they appear to be involved with the nervous system. Thus, histamine depresses sympathetic neurotransmission in the guinea pig mesenteric artery by interacting with H.sub.3 receptors on the perivascular nerve terminals (Ishikawa and Sperelakis, Nature 327:158 (1987)). This important observation suggests that histamine may control the release of other neurotransmitters (Tamura et al., Neuroscience 25:171 (1988)). Inhibitory histamine H.sub.3 receptors also exist in the guinea pig ileum where their role appears to be to modify the magnitude of histamine contraction, rather than affecting histamine release (Trzeciakowski, J. Pharmacol. Exp. Therapy 243:847 (1987)). Particularly intriguing is the discovery of H.sub.3 receptors in the lung (Arrang et al. supra (1987)). The presence of histamine H.sub.3 receptors in the lung raises the question of whether they control histamine release in anaphylaxis and whether they may be manipulated to provide therapy in asthma. Indeed it has been suggested that H.sub.3 receptors may have a modulating role on excitatory neurotransmission in airways. Generally, however, H.sub.3 receptor inhibition tends to increase histamine activity, with potentially detrimental effects. Thus, it is desirable to avoid introducing H.sub.3 receptor antagonists that act on peripheral tissues.
Histamine H.sub.3 receptor activation was found to inhibit acetylcholine release in a guinea pig ileum model (Poli et al., Agents and Actions 33: 167-169). Selective H.sub.3 -receptor blockers reversed the histamine-induced inhibitory effect. Histamine also decreased serotonin release; this effect was reversed with an H.sub.3 -antagonist, and was suggested to operate via the histamine H.sub.3 -receptors (Schlicker et al., Naunyn-Schmiedaberg's Arch. Pharmacal. 337:588-590 (1988). Activation of H.sub.3 -receptors was found to inhibit excitatory presynaptic potentials (Arrang et al., J. Neurochem. 51:105 (1988)).
One reported highly specific competitive antagonist of histamine H.sub.3 receptors is thioperamide (Arrang et al., supra (1987)). Although thioperamide is a very potent antagonist in vitro (K.sub.i =4.3 nmol/L), relatively high doses are required in vivo to inhibit histamine release from the brain in rats (Ganellin et al., Collect. Czech. Chem. Commun. 56:2448-2455 (1991)). Ganellin et al. suggests that this most probably results from poor penetration through the blood-brain-barrier by this peramide, although the pharmacokinetic properties of thioperamide may also play a role. Moreover, the thiourea functionality found in thioperamide may result in higher intrinsic toxicity of thioperamide.
Thiourea-containing drugs are known to be associated with undesirable side effects in clinical use. For example, with thiourea-containing drug molecules that are used to treat hyperthyroidism, agranulocytosis is known to be a serious, and occasionally fatal, toxic effect in clinical use (see, e.g., Brimblecombe et al. Gastroenterology 74:339-346 (1978)). The thiourea-containing histamine H.sub.2 -receptor antagonist metiamide caused a low incidence of granulocytopenia in peptic ulcer patients and was withdrawn from clinical use (Forrest et al., Lancet 1: 392-393 (1975)). In high dose, repeated dose toxicological studies in dogs, incidences of agranulocytosis were seen at 162 mg/kg/day (Brimblecombe et al., "Toxiology of Metiamide," International Symposium on Histamine H.sub.21 --Receptor Antogonists, Wood and Simpkins, Smith Kline & French, pp. 53-72 (1973)). A proportion of dogs (&lt;10%) died acutely with pulmonary edema and pleural effusion. The metiamide isostere cimetidine, in which the thiourea group was replaced by an alternative group (cyanoguanidine), did not cause granulocytopenia, or any other side effects in animal toxicity studies or in clinical usage by multimillions of patients, indicating that the toxicological problems with metiamide could be attributed to the presence of the thiourea group (Brimblecomb et al., supra). It is likely that the thiourea functionality, with its association with toxiological phenomena and its likelihood of inducing undesirable side effects, could limit the clinical development of thioperamide.
Although some predictions have been made concerning the ability of molecules to pass through the blood brain barrier, these predictions are at best speculative. The rate and extent of entry of a compound into the brain are generally considered to be determined primarily by partition coefficient, ionization constant(s) and molecular size. No single partition solvent system has emerged as a universally applicable model for brain penetration, although the octanol water system has received particular attention, and Hansch and coworkers have suggested that a partition coefficient in this system of about 100 is optimal for entry into the central nervous system (CNS) (Glave and Hansch, J. Pharm. Sci., 61:589 (1972); Hansch et al., J. Pharm. Sci., 76:663 (1987)). Comparisons between known H.sub.2 antagonists, however, suggest that there is no such simple relationship between their brain penetration and octanol water partition coefficients (Young t al., J. Med. Chem. 31:656 (1988)). The comparison of the ability of histamine H.sub.2 receptor antagonists to cross the blood brain barrier suggests that brain penetration may increase with decreasing over-all hydrogen binding ability of a compound (Young et al., supra). However, optimizing H.sub.2 receptor antagonists to improve brain penetration reduced antagonist potency (Young et al., supra). Thus it is fundamentally difficult to optimize both blood brain barrier permeability and function of a compound.
It is therefore an object of the present invention to provide novel potent histamine H.sub.3 -receptor antagonists that are better able to penetrate the blood-brain-barrier than previously reported compounds.
Further it is an object of the present invention to provide novel potent histamine H.sub.3 -receptor antagonists that have reduced toxicity compared to other known H.sub.3 antagonists.
Another object of the present invention is to provide histamine H.sub.3 -receptor antagonists that will act selectively on the brain and have limited activity on H.sub.3 receptors in peripheral tissues.
It is yet another object of the present invention to provide a novel class of histamine H.sub.3 -receptor antagonists.